Abstract 5434: Discovery of SCR-7952, a novel, potent and high selective MAT2A inhibitor shows robust anti-tumor activities and better safety profile
Authors: Feng Zhou, Feng Tang, Zhiyong Yu, Zhen Li, Wenqing Yang, Liting Xue, Ping Chen, Renhong Tang
Journal: Cancer Research (2022)

Abstract The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was identified as a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deleted cancers. The co-deletion of MTAP and CDKN2A was observed in approximately 15% of all cancers and predicted worse outcomes, which provides MAT2A a potential therapeutic target. AG-270, a first MAT2A inhibitor, is currently evaluated in early clinical study. Given the inhibitory activity on UGT1A1, a bilirubin uridine diphosphate glucuronosyl transferase regulating the homeostasis of bilirubin, treatment of AG-270 led to the bilirubin increase in patients, which limited the further dose escalation. Therefore, to avoid those off-targeted side effects and maximize benefit from the MAT2A targeted therapy, it is necessary to develop a new generation of MAT2A inhibitor with better activity and higher selectivity, especially, removal of UGT1A1 activity. Here, we report SCR-7952 is a novel MAT2A inhibitor with greater potency and higher selectivity. In biochemical assay, SCR-7952 exhibited potent inhibitory activity on MAT2A enzyme with IC50 of 21 nM, which was more potent than AG-270 (IC50, 68 nM). In HCT116 MTAP-/- cells, SCR-7952 strongly inhibited the cellular SAM production with IC50 of 2 nM, which was significantly more potent than AG-270 (IC50, 6 nM). And SCR-7952 potently inhibited HCT116 MTAP-/- cell growth with IC50 of 53 nM, which was almost 6-fold more potent than AG-270 tested in parallel (IC50, 300 nM). Meanwhile, SCR-7952 displayed more than 20-fold selectivity over the HCT116 parent cells on proliferation assay. However, AG-270 only demonstrated 4-fold selectivity in the same assay. Furthermore, inhibition of SCR-7952 on a panel of 47 life-dependent targets was determined at 10 μM, result showed that there is no significant inhibition observed. In addition to MTAP KO cells, SCR-7952 showed potently inhibited cell growth in multiple cell lines with natural MTAP-deficiency. SCR-7952 revealed excellent oral bioavailability and PK properties in pre-clinical species. In the HCT-116 MTAP-/- xenograft model, SCR-7952 demonstrated robust anti-tumor activity and achieved 72% tumor growth inhibition (TGI) at 1 mpk, QD, which was more potent than AG-270 (TGI 56% at 200 mpk, QD). Furthermore, SCR-7952 was well tolerant and no elevation of bilirubin was observed. In contrast, AG-270 at 200mpk resulted in significant increase of bilirubin. In conclusion, the above data demonstrate that SCR-7952 is a more potent and higher selective MAT2A, and will be filed IND in 2022. Citation Format: Feng Zhou, Feng Tang, Zhiyong Yu, Zhen Li, Wenqing Yang, Liting Xue, Ping Chen, Renhong Tang. Discovery of SCR-7952, a novel, potent and high selective MAT2A inhibitor shows robust anti-tumor activities and better safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5434.